title: Epiregulin expression by Ets-1 and ERK signaling pathway in Ki-ras-transformed cells.
abstract: Epiregulin belongs to the epidermal growth factor family, binds to the epidermal growth factor receptor, and its expression is upregulated in various cancer cells, but the regulatory mechanism is unclear. We investigated the regulatory mechanism of epiregulin expression in Ki-ras-transformed cancer cells. In 267B1/Ki-ras cells, the RAF/MEK/ERK pathway was constitutively activated, epiregulin was up-regulated, and the expression and phosphorylation of Ets-1 were augmented. The inhibition of ERK by PD98059 decreased epiregulin and Ets-1 expression and suppressed the growth of 267B1/Ki-ras cells. A chromatin immunoprecipitation assay demonstrated that Ets-1 was bound to human epiregulin promoter, and this binding was abolished by PD98059. Silencing of Ets-1 by RNA interference decreased cellular epiregulin transcript expression. We suggest that the Ki-ras mutation in 267B1 prostate cells constitutively activates the RAF/MEK/ERK pathway and induces the activation of the Ets-1 transcription factor, ultimately leading to the increased expression of epiregulin.
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, 1 Hwayng-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.
authors.forename: Min-Chul
authors.initials: MC
authors.lastname: Cho
authors.forename: Hee-Sook
authors.initials: HS
authors.lastname: Choi
authors.forename: Sojung
authors.initials: S
authors.lastname: Lee
authors.forename: Bo Yeon
authors.initials: BY
authors.lastname: Kim
authors.forename: Mira
authors.initials: M
authors.lastname: Jung
authors.forename: Sue Nie
authors.initials: SN
authors.lastname: Park
authors.forename: Do-Young
authors.initials: DY
authors.lastname: Yoon
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000235:genetics*; D066260:Epiregulin; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics
chemical_list: C587880:EREG protein, human; C494041:ETS1 protein, human; D066260:Epiregulin; C587881:Ereg protein, mouse; D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D050784:Proto-Oncogene Protein c-ets-1; D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one